Abstract Toxicant exposures early in life adversely affect health outcomes in both animal models and humans, in part due to epigenetic mechanisms. Accumulating studies also indicate that exposures' impact on the epigenome can be tissue and even cell specific. Yet, toxicoepigenetic animal studies are often conducted with single tissues in bulk and/or limited epigenomic targets (e.g. DNA methylation). Additionally, epigenetic epidemiology analysis of toxicants is almost always restricted to biologically available, ?surrogate? (e.g. blood) samples. Using a combination of toxicological and epidemiological approaches, the first of two overarching goals of this Revolutionizing Innovative, Visionary Environmental Health Research (RIVER) application is to advance the understanding of the effects of representative perinatal exposures (e.g. metals including lead and endocrine active compounds including phthalates) on the epigenome and longitudinal health risks. To accomplish this, we will use human physiologically relevant mouse models and longitudinal human birth cohort samples alongside targeted and unbiased approaches to evaluate DNA methylation, non-coding RNA, chromatin structure, and gene expression in both sexes in multiple tissues, incorporating single cell approaches when relevant. Ultimately, we seek to identify tissue-specific epigenomic signatures of exposures contributing to disease susceptibility as well as regions of the epigenome that may be interrogated with the use of surrogate tissues. While precision modification of the epigenome holds great promise to modify environmentally induced changes and reduce disease risk, it is currently out of reach using common available global (e.g. azacytidine) and targeted (e.g. TALENs, CRISPR) systems. Thus, our second overarching goal is to advance the development of a suite of tools, based on the PIWI-interacting RNA (piRNA) system to transform precision environmental health, while avoiding drawbacks of current technology. In mice, we have shown that piRNA and associated processing machinery are present and active in somatic tissues, especially the brain, in contrast to prior belief that the piRNA suppression system was restricted to the germ-line. Evidence from our viable yellow agouti (Avy) mouse experiments supports piRNA-based DNA methylation induction in vivo. Thus, we propose to use this class of RNA to develop precision environmental health tools to target specific genes and loci for stable, mitotically heritable, silencing in somatic cells. First, we will evaluate piRNA/PIWIL machinery across somatic human tissues to prioritize cell types with high endogenous piRNA machinery for epigenetic editing. Then, we will develop synthetic piRNAs to target DNA methylation in vitro in exposed rodent and human cell lines. The research will expand the repertoire of human epigenome editing tools resulting in therapeutics to treat a broad array of environmental and epigenetic diseases including imprinted gene disorders and cancer. The vision for the flexible and sustained RIVER support is to innovate the field of environmental epigenomics, develop translational tools for precision epigenome editing, and be a resource for research and training.